Preparation of Deoxynucleosides, Deoxynucleotides and Oligodeoxynucleotides Bearing Adducts of PAH Diol Epoxides at the N<sup>6</sup>Position of Adenine

Harris, Thomas M.; Harris, Constance M.; Kim, Seong J.; Han, Shin; Kim, Hye Young; Zhou, Liang

doi:10.1080/10406639408031162

Cited by 7 publications

(4 citation statements)

References 8 publications

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“…The notion that sequence effects might be operative came from structural ( , ) and site-specific mutagenesis studies () with the adenyl N 6 benzo[ a ]pyrene SRSR (61,2) and (61,3) adducts, located at the first and second adenines of the ras 61 oligodeoxynucleotide. For those BP adducts, the adduct located at the (61,2) position exhibited a single conformation, whereas the adduct located at the (61,3) position was described as a mixture of two conformations in equilibrium ( , ). Those sequence-dependent differences in structure paralleled sequence-dependent differences in mutagenesis.…”

Section: Discussionmentioning

confidence: 99%

“…The ras 61 oligodeoxynucleotide facilitates investigation as to how DNA sequence and PAH ring structure each modulate adduct conformation in solution. The development of a nonbiomimetic synthesis enabled large-scale production of site-specific PAH adducts in the ras 6 oligodeoxynucleotide while eliminating problems in controlling the regioselectivity of adduction ( − ). This oligodeoxynucleotide contains the codon 61 sequence for the human N- ras protooncogene (underlined).…”

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confidence: 99%

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Intercalation of the (1R,2S,3R,4S)-N⁶-[1-(1,2,3,4- Tetrahydro-2,3,4-trihydroxybenz[a]anthracenyl)]-2‘-deoxyadenosyl Adduct in the N-ras Codon 61 Sequence: DNA Sequence Effects

Tamura

Wilkinson

et al. 2001

Biochemistry

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The structure of the bay region (1R,2S,3R,4S)-N6-[1-(1,2,3,4-tetrahydro-2,3,4-trihydroxybenz[a]anthracenyl)]-2'-deoxyadenosyl adduct at X(7) of 5'-d(CGGACAXGAAG)-3'.5'-d(CTTCTTGTCCG)-3', incorporating codons 60, 61 (underlined), and 62 of the human N-ras protooncogene, was determined by NMR. This was the bay region benz[a]anthracene RSRS (61,3) adduct. The BA moiety intercalated above the 5'-face of the modified base pair. NOE connectivities between imino protons were disrupted at T16 and T17. Large chemical shifts at the lesion site were consistent with ring current shielding arising from the BA moiety. A large chemical shift dispersion was observed for the BA aromatic protons. An increased rise of 8.17 A was observed between base pairs A6 x T17 and X7 x T(16). The PAH moiety stacked with the purine ring of A6, the 5'-neighbor nucleotide. This resulted in buckling of the 5'-neighbor A6 x T17 base pair, evidenced by exchange broadening for the T17 imino resonance. It also interrupted sequential NOE connectivities between nucleotides C5 and A6. The A6 deoxyribose ring showed an increased percentage of the C3'-endo conformation. This differed from the bay region BA RSRS (61,2) adduct, in which the lesion was located at position X6 [Li, Z., Mao, H., Kim, H.-Y., Tamura, P. J., Harris, C. M., Harris, T. M., and Stone, M. P. (1999) Biochemistry 38, 2969-2981], but was similar to the benzo[a]pyrene BP SRSR (61,3) adduct [Zegar I. S., Chary, P., Jabil, R. J., Tamura, P. J., Johansen, T. N., Lloyd, R. S., Harris, C. M., Harris, T. M., and Stone, M. P. (1998) Biochemistry 37, 16516-16528]. The altered sugar pseudorotation at A6 appears to be common to both bay region BA RSRS (61,3) and BP SRSR (61,3) adducts. It could not be discerned if the C3'-endo conformation at A6 in the BA RSRS (61,3) adduct altered base pairing geometry at X7 x T16, as compared to the C2'-endo conformation. The structural studies suggest that the mutational spectrum of this adduct may be more complex than that of the BA RSRS (61,2) adduct.

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Section: Discussionmentioning

confidence: 99%

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Intercalation of the (1R,2S,3R,4S)-N⁶-[1-(1,2,3,4- Tetrahydro-2,3,4-trihydroxybenz[a]anthracenyl)]-2‘-deoxyadenosyl Adduct in the N-ras Codon 61 Sequence: DNA Sequence Effects

Tamura

Wilkinson

et al. 2001

Biochemistry

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“…The benzo[ a ]pyrene and benz[ a ]anthracene-modified oligodeoxynucleotides were synthesized through a nonbiomimetic procedure in which the amino triols derived from the respective diol epoxides were reacted with oligodeoxynucleotides containing 6-fluoroinosine at position X 6 ( − ). The modified oligodeoxynucleotides were purified by reverse-phase HPLC.…”

Section: Methodsmentioning

confidence: 99%

Altered Electrophoretic Migration of Polycyclic Aromatic Hydrocarbon and Styrene Oxide Adducts at Adenine N⁶ Correlates with Adduct-Induced Structural Disorder

Harris

et al. 1999

Chem. Res. Toxicol.

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Site-specific bay region benzo[a]pyrene (7R,8S,9R,10S)-N(6)-[10-(7,8, 9,10-tetrahydro-7,8,9-trihydroxybenzo[a]pyrenyl)]-2'-deoxyadeno syl, (7S,8R,9S,10R)-N(6)-[10-(7,8,9,10-tetrahydro-7,8, 9-trihydroxybenzo[a]pyrenyl)]-2'-deoxyadenosyl, (7S,8R,9R, 10S)-N(6)-[10-(7,8,9,10-tetrahydro-7,8, 9-trihydroxybenzo[a]pyrenyl)]-2'-deoxyadenosyl, and (7R,8S,9S, 10R)-N(6)-[10-(7,8,9,10-tetrahydro-7,8, 9-trihydroxybenzo[a]pyrenyl)]-2'-deoxyadenosyl adducts, bay region benz[a]anthracene (1R,2S,3R,4S)-N(6)-[1-(1,2,3,4-tetrahydro-2,3, 4-trihydroxybenz[a]anthracenyl)]-2'-deoxyadenosyl and (1S,2R,3S, 4R)-N(6)-[1-(1,2,3,4-tetrahydro-2,3, 4-trihydroxybenz[a]anthracenyl)]-2'-deoxyadenosyl adducts, non-bay region benz[a]anthracenyl (8S,9R,10S,11R)-N(6)-[11-(8,9,10, 11-tetrahydro-8,9,10-trihydroxybenz[a]anthracenyl)]-2'-de oxyadenosyl and (8R,9S,10R,11S)-N(6)-[11-(8,9,10,11-tetrahydro-8,9, 10-trihydroxybenz[a]anthracenyl)]-2'-deoxyadenosyl adducts, and the R- and S-adducts of styrene oxide were located in the ras61 oligodeoxynucleotide and examined with respect to electrophoretic mobility. The results were compared to NMR structural data, and to site-specific mutagenesis data and in vitro DNA replication assays for the same adducts. There was a correlation between adducts having lower electrophoretic mobility and greater disorder at the adduct site as monitored by NMR. The disorder combined with the lower electrophoretic mobilities suggested that these adducts induced flexible hinge joints in the DNA rather than static bending. Usually, these were adenine N(6) adducts having S-stereochemistry at the benzylic carbon. The results also revealed a possible role for the bay region ring in stabilizing adenyl N(6) benz[a]anthracene adducts with respect to hinging at the adduct site. On the other hand, there was not a simple relationship between altered electrophoretic mobility and mutagenesis or DNA replication.

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“…As an initial step toward answering this question, we undertook the synthesis of oligonucleotides containing an N 2 dGuo or N 6 dAdo adduct of 2 at a single site. We anticipated that the nonbiomimetic approach in which an amine equivalent of the electrophile is reacted with an oligonucleotide containing a halonucleoside (Scheme ) would work well for these syntheses as it had for our previous work on site- and stereospecific adducts of PAH diol epoxides ( , ). This paper describes the synthesis and characterization of nucleosides and oligonucleotides containing adducts of 6-methylbenzo[ a ]pyrene on the exocyclic amino groups of adenine and guanine.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Nucleosides and Oligonucleotides with a Benzo[a]pyren-6-ylmethyl Adduct at Adenine N⁶ or Guanine N²

Kim

Cooper

Nechev

et al. 2001

Chem. Res. Toxicol.

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Benzo[a]pyrene (1) can be converted to reactive electrophilic species by a number of metabolic pathways, of which the route to the mutagenic and carcinogenic diol epoxide(s) is the best studied. An alternative and interesting pathway to a highly genotoxic electrophile is through alkylation at the 6 position to 6-methylbenzo[a]pyrene (2) followed by oxidation of the methyl group to give 6-hydroxymethylbenzo[a]pyrene (3). Esterification of 3, especially to sulfate ester 4, gives compounds which are both mutagenic and carcinogenic. The major DNA adduct identified from exposure of rats and mice to 4 is the guanine N(2) adduct [2'-deoxy-N(2)-(benzo[a]pyren-6-ylmethyl)guanosine, 5] which is also formed via activation of 2 to a radical cation species by horseradish peroxidase/H(2)O(2) or iodine. To study the biological and structural properties of this adduct and the analogous adenine N(6) adduct (6), a nonbiomimetic synthesis of the adducted nucleosides 5 and 6 has been developed and has been extended to preparation of oligonucleotides containing 5 or 6 at a single site.

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Preparation of Deoxynucleosides, Deoxynucleotides and Oligodeoxynucleotides Bearing Adducts of PAH Diol Epoxides at the N⁶Position of Adenine

Cited by 7 publications

References 8 publications

Intercalation of the (1R,2S,3R,4S)-N⁶-[1-(1,2,3,4- Tetrahydro-2,3,4-trihydroxybenz[a]anthracenyl)]-2‘-deoxyadenosyl Adduct in the N-ras Codon 61 Sequence: DNA Sequence Effects

Intercalation of the (1R,2S,3R,4S)-N⁶-[1-(1,2,3,4- Tetrahydro-2,3,4-trihydroxybenz[a]anthracenyl)]-2‘-deoxyadenosyl Adduct in the N-ras Codon 61 Sequence: DNA Sequence Effects

Altered Electrophoretic Migration of Polycyclic Aromatic Hydrocarbon and Styrene Oxide Adducts at Adenine N⁶ Correlates with Adduct-Induced Structural Disorder

Synthesis and Characterization of Nucleosides and Oligonucleotides with a Benzo[a]pyren-6-ylmethyl Adduct at Adenine N⁶ or Guanine N²

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Preparation of Deoxynucleosides, Deoxynucleotides and Oligodeoxynucleotides Bearing Adducts of PAH Diol Epoxides at the N6Position of Adenine

Cited by 7 publications

References 8 publications

Intercalation of the (1R,2S,3R,4S)-N6-[1-(1,2,3,4- Tetrahydro-2,3,4-trihydroxybenz[a]anthracenyl)]-2‘-deoxyadenosyl Adduct in the N-ras Codon 61 Sequence: DNA Sequence Effects

Intercalation of the (1R,2S,3R,4S)-N6-[1-(1,2,3,4- Tetrahydro-2,3,4-trihydroxybenz[a]anthracenyl)]-2‘-deoxyadenosyl Adduct in the N-ras Codon 61 Sequence: DNA Sequence Effects

Altered Electrophoretic Migration of Polycyclic Aromatic Hydrocarbon and Styrene Oxide Adducts at Adenine N6 Correlates with Adduct-Induced Structural Disorder

Synthesis and Characterization of Nucleosides and Oligonucleotides with a Benzo[a]pyren-6-ylmethyl Adduct at Adenine N6 or Guanine N2

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Preparation of Deoxynucleosides, Deoxynucleotides and Oligodeoxynucleotides Bearing Adducts of PAH Diol Epoxides at the N⁶Position of Adenine

Intercalation of the (1R,2S,3R,4S)-N⁶-[1-(1,2,3,4- Tetrahydro-2,3,4-trihydroxybenz[a]anthracenyl)]-2‘-deoxyadenosyl Adduct in the N-ras Codon 61 Sequence: DNA Sequence Effects

Intercalation of the (1R,2S,3R,4S)-N⁶-[1-(1,2,3,4- Tetrahydro-2,3,4-trihydroxybenz[a]anthracenyl)]-2‘-deoxyadenosyl Adduct in the N-ras Codon 61 Sequence: DNA Sequence Effects

Altered Electrophoretic Migration of Polycyclic Aromatic Hydrocarbon and Styrene Oxide Adducts at Adenine N⁶ Correlates with Adduct-Induced Structural Disorder

Synthesis and Characterization of Nucleosides and Oligonucleotides with a Benzo[a]pyren-6-ylmethyl Adduct at Adenine N⁶ or Guanine N²